Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2a, A2b, and A3, all of which modulate important physiological processes. For example, A1 adenosine receptor agonists modulate the cardiostimulatory effects of catecholamine, thus slowing the heart rate, and also prolong impulse propagation through the AV node. Thus, stimulation of A1 receptors provides a method of treating supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter. A2A adenosine receptors modulate coronary vasodilation, A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148–153), and A3 adenosine receptors modulate cell proliferation processes.
A1 adenosine receptor antagonists have pronounced effects on the kidney, and have shown to be potent diuretics and natriuretics with little effective on potassium excretion. Thus, they are renal protective, useful for the treatment of renal failure, renal dysfunction, nephritis, hypertension, and edema. A1 adenosine receptor antagonists are also useful for treating dementias such as Alzheimers disease, and for treating stress, depression, cardiac arrhythmia, restoration of cardiac function, congestive heart failure, asthma, and respiratory disorders. They also reduce ischemia-induced injury of the brain, heart and kidney, and diarrhea.
It is desired to provide compounds that are potent A1 adenosine receptor antagonists, useful in the treatment of various disease states related to modulation of the A1 adenosine receptor, in particular useful as diuretics.
In U.S. patent application Ser. No. 10/184,494, filed Jun. 27, 2002, novel A2B adenosine receptor antagonists were disclosed. It has now surprisingly been found that a subgroup of the compounds disclosed in this application also have the property of being A1 receptor adenosine receptor antagonists and, in fact, are actually more active as A1 receptor antagonists. Thus, the compounds of Formula I are both A2B-antagonists and A1-antagonists, and consequently are effective in the treatment of conditions that respond to administration of A2B adenosine receptor antagonists as well as those conditions listed above for A1 antagonists. Conditions that respond to administration of A2B adenosine receptor antagonists include diarrhea, atherosclerosis, restenosis, diabetic retinopathy, cancer, senile dementia, Alzheimer's disease, Parkinson's disease, traumatic brain injury, and Type I hypersensitivity reactions, including asthma, atopic eczema, and hay fever.